The candidates long-term goal is to explore novel therapeutic strategies to improve clinical outcomes in patients with sepsis by investigating the role of macrolide therapy as an immunomodulator. The proposed career development plan integrates didactic coursework and tutorials with mentored research experience in the design and conduct of pharmacoepidemiological and randomized control trials to provide the candidate the necessary components for a successful career in patient-oriented research. The candidate's educational aims are to 1) acquire sufficient knowledge to conduct pharmacoepidemiology studies using large secondary databases and randomized control trials to study the effect of novel immunomodulators for patients with sepsis; 2) understand the potential physiologic and genetic mechanisms of novel immunomodulatory treatments; 3) translate research findings into clinical practice with the goal of improving the short and long term outcomes of patients with sepsis. Under the mentorship of Drs. Anzueto, Coalson and Mortensen, the candidate will acquire the knowledge and skills required to investigate the effects of macrolide therapy as an immunomodulator in patients with sepsis. The objective of the proposed research is to examine whether the use of a macrolide in addition to standard therapy is associated with improved host immune response, and how this response will impact short and long-term clinical outcomes. The central hypothesis is that macrolide use in patients with pulmonary and extrapulmonary sources of severe sepsis is associated with improved immune response and other clinical outcomes. This proposal will facilitate and provide pilot data for future studies that will evaluate the potential impact of immunomodulatory therapies on improving clinical outcomes for patients with severe sepsis. Three research aims will be examined: 1) The association between macrolide therapy and clinical outcomes, including short (30-day) and long-term (3, 6 and 12 months) mortality, length of stay, and rates of mechanical ventilation for patients with severe sepsis; 2) The effects of macrolide therapy on inflammatory markers and clinical outcomes in patients with severe sepsis; 3) The impact of macrolide use vs. non-use on long-term inflammatory markers and survival in patients with severe sepsis. The approach is innovative, because it utilizes macrolides as immunomodulators for an indication other than community-acquired pneumonia in order to improve outcomes in patients with severe sepsis. The proposed research is significant, because it will improve the level of understanding of the possible mechanisms of immunomodulation and the impact of macrolide therapy in patients with severe infections.